Head and neck squamous cell carcinomas (HNSCC), including cancers of the upper aerodigestive tract, are one of the most common cancers worldwide, with an estimated 52,000 new cases in the United States in 20111. While treatment of early-stage HNSCC with radiation therapy and/or surgery is often successful in treating primary tumors, many patients develop second primary tumors (SPT) or experience recurrence, resulting in a 5-year survival rate of approximately 50%, a rate which has remained constant for decades2. To date, all-trans retinoic acid (RA) and its isoforms are perhaps the most thoroughly studied agents in the treatment and prevention of SPT and HNSCC recurrence. The rate-limiting enzyme in endogenous RA synthesis from retinol (vitamin A), aldehyde dehydrogenase 1a2 (ALDH1a2), has recently been shown to act as a tumor suppressor in human prostate cancer20. Moreover, ALDH1a2 transcript levels were dramatically reduced in RNA data sets from over 500 human HNSCC samples. We aim to investigate the role of ALDH1a2 as an inhibitor of HNSCC tumorigenesis. We hypothesize that ALDH1a2 expression inhibits the development of HNSCC by increasing endogenous RA production and signaling. To test this hypothesis, I will conduct a multi-faceted project examining the effect of ALDH1a2 expression on HNSCC both in vitro and in vivo. In Aim 1, I will determine if ALDH1a2 expression alters the tumorigenic phenotype of several human HNSCC lines by infecting them with a retroviral ALDH1a2 expression vector. My preliminary results indicate that ALDH1a2 expression significantly inhibits HNSCC cell growth and clonogenicity in vitro. In Aim 2 I will create transgenic mice that inducibly (via tetracycline regulation) express ALDH1a2 in the oral mucosa, and then determine whether this induction reduces the incidence and/or severity of oral cavity carcinogenesis in our carcinogen-induced murine model of human oral carcinogenesis. Furthermore, in both aims I will compare the effects of endogenous ALDH1a2 expression to those of treatment with exogenous RA. By completing these aims I will determine if ectopic ALDH1a2 expression can inhibit the malignant phenotype and onset of oral cavity cancer, and ascertain whether enhanced production of endogenous RA is more inhibitory with respect to oral cavity carcinogenesis than addition of exogenous RA. This research will not only further our understanding of retinoid signaling and chemoprevention in HNSCC, but may also provide the first evidence for ALDH1a2 as an inhibitor of tumor development in HNSCC.